Patients with mutations in the von Hippel-Lindau gene (VHL) develop a pleomorphic familial tumor syndrome that is characterized by the development of highly vascularized tumors with different biological behaviors such as CNS hemangioblastomas and clear cell renal cell cancers (RCC) which are often preceded by renal cysts. Recently the VHL protein (pVHL) has been found to regulate the stability of hypoxia-inducible-factor (HIF). However not all aspects of this disease, such as the malignant phenotype of RCCs, can be easily explained by this interaction. A VHL mouse model would provide a powerful tool for the identification of molecular factors that are critical for the pathogenesis of the VHL phenotype. However, the development of such a model was hampered by the fact that conventional VHL knockout mice died during midgestation from placental failure, which initially precluded a functional analysis of this gene in the adult. In order to overcome this problem with embryonic lethality, the Principal Investigator has generated mice that allow tissue-specific deletions of Vhl in the adult through Cre/loxP-mediated recombination. Several conditional mouse mutants have been generated. Inactivation of Vhl in the liver for example leads to the accumulation of neutral lipids in hepatocytes, proliferation of endothelial cells, as well as erythrocytosis, all of which is consistent with pVHL's role in the regulation of HIF. At the moment it remains unclear whether the phenotypes that were observed in conditional VHL knockout mice can be solely attributed to the up-regulation of HIF-1 dependent target genes and whether pVHL controlled molecular pathways exist that are not regulated by HIF. The studies proposed here will address these questions and aim at defining the critical molecular mediators of the VHL phenotype by generating several tissue-specific conditional mouse mutants that are double deficient in Vhl and Hif-1. The molecular analysis of these mutants with microarrays might provide important insights into the regulation of growth and apoptosis of renal tubule cells. The proposed investigations represent a continuation and expansion of research that was initially described in the applicant's K08 and is based on data that were generated under this grant. They will be carried out in the laboratory of Dr. Volker H. Haase, who is an Assistant Professor of Medicine in the University of Pennsylvania's Renal Division. Dr. Michael Madaio, Professor of Medicine, will function as Dr. Haase's mentor for this grant.